1α-Hydroxylase transactivation by γ-interferon in murine macrophages requires enhanced C/EBPβ expression and activation

Esteban, Luis; Vidal, Marcos; Dusso, Adriana

doi:10.1016/j.jsbmb.2004.03.092

Cited by 47 publications

(30 citation statements)

References 24 publications

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“…These findings and calcitriol efficacy in suppressing parathyroid 23 and A431 cell growth 38 suggest novel calcitriol antiproliferative properties. Calcitriol could either downregulate TGF-␣/EGFR induction of LIP synthesis or prevent LIP-induced decreases in cellular LAP/LIP ratio through induction of LAP, as demonstrated in osteoblasts, 22,39 renal cells, 22 and monocyte-macrophages, 40,41 the last through a VDR-mediated mechanism. 40 In SH, LIP antagonism on LAP transactivation of the VDR gene could mediate the reduction in VDR levels upon EGFR activation.…”

Section: Discussionmentioning

confidence: 99%

EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

Arcidiacono

Sato²,

Alvarez-Hernandez³

et al. 2008

Journal of the American Society of Nephrology

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Calcitriol, acting through vitamin D receptors (VDR) in the parathyroid, suppresses parathyroid hormone synthesis and cell proliferation. In secondary hyperparathyroidism (SH), VDR content is reduced as hyperplasia becomes more severe, limiting the efficacy of calcitriol. In a rat model of SH, activation of the EGF receptor (EGFR) by TGF-␣ is required for the development of parathyroid hyperplasia, but the relationship between EGFR activation and reduced VDR content is unknown. With the use of the same rat model, it was found that pharmacologic inhibition of EGFR activation with erlotinib prevented the upregulation of parathyroid TGF-␣, the progression of growth, and the reduction of VDR. Increased TGF-␣/EGFR activation induced the synthesis of liver-enriched inhibitory protein, a potent mitogen and the dominant negative isoform of the transcription factor CCAAT enhancer binding protein-␤, in human hyperplastic parathyroid glands and in the human epidermoid carcinoma cell line A431, which mimics hyperplastic parathyroid cells. Increases in liver-enriched inhibitory protein directly correlated with proliferating activity and, in A431 cells, reduced VDR expression by antagonizing CCAAT enhancer binding protein-␤ transactivation of the VDR gene. Similarly, in nodular hyperplasia, which is the most severe form of SH and the most resistant to calcitriol therapy, higher TGF-␣ activation of the EGFR was associated with an 80% reduction in VDR mRNA levels. Thus, in SH, EGFR activation is the cause of both hyperplastic growth and VDR reduction and therefore influences the efficacy of therapy with calcitriol.

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Section: Discussionmentioning

confidence: 99%

EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

Arcidiacono

Sato²,

Alvarez-Hernandez³

et al. 2008

Journal of the American Society of Nephrology

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“…CYP27B1 produced by macrophages, unlike renal CYP27B1, is not suppressed by elevated 1,25(OH) 2 D 3 but is upregulated by immune stimuli [interferon-␥ and lipopolysaccharide (LPS)]. Regulation by immune stimuli has been reported to involve multiple pathways (including JAK/STAT and NFB) and to require binding of the C/EBP␤ transcription factor to the mouse and human CYP27B1 genes (136,429). Further evidence of immune derived CYP27B1 is provided by recent studies showing that reconstitution of the hematopoietic cell population from wild-type (WT) mice in Cyp27b1 knockout mice protects mice from colitis (342).…”

Section: B Cyp27b1mentioning

confidence: 99%

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

Christakos

Dhawan

Verstuyf

et al. 2016

Physiological Reviews

1,478

1,234

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, [1,25(OH) 2 D 3 ] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH) 2 D 3 action involves the direct binding of the 1,25(OH) 2 D 3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH) 2 D 3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH) 2 D 3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease.

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“…This is akin to testosterone as the bioactive precursor for dihydrotestosterone and estradiol in target tissues. For 25-OHD, the inflamed endothelium (40) and activated cells of the monocyte/macrophage lineage (41) are the most studied nonrenal targets for 1,25(OH) 2 D 3 synthesis (39). The regulated contributions of these nonrenal sources to serum 1,25(OH) 2 D 3 levels and vitamin D signaling in vascular health are not known.…”

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confidence: 99%

Calciotropic Hormones and Arterial Physiology

Towler¹

2007

Journal of the American Society of Nephrology

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V ascular calcification increasingly afflicts our aging and dysmetabolic population (1). In the past decade, vascular calcification has emerged as an actively regulated form of calcified tissue metabolism, resembling mineralization of endochondral and membranous bone (1). Demer and colleagues (2) were the first to provide molecular insights into disease pathobiology. In 1993, they identified expression of the powerful bone morphogen, BMP2, in calcium-laden type Vb atherosclerotic plaques. Detailed studies have confirmed contributions of osteogenic BMP2 and Wnt signaling cascades not only in atherosclerotic disease (2) but also during medial artery calcification of diabetes (3) and calcific aortic stenosis (4). Executive cell types that are familiar to bone biologists are seen in calcifying macrovascular specimens, controlling calcified matrix remodeling via paracrine signals that include osteopontin, matrix Gla protein, and inorganic pyrophosphate (1,3,5). Ectopic skeletal morphogens divert aortic mesoangioblasts, mural pericytes, and valve myofibroblasts to osteogenic fates (1,3,6). Ectopic vascular expression of pro-osteogenic morphogens is entrained to physiologic stimuli that promote calcification (1,3). Inflammation, mechanical shear, oxidative stress, hyperphosphatemia, and elastinolysis provide stimuli that promote osteogenic matrix remodeling and compromise vascular defenses that limit calcium deposition (1,3).In ESRD, a "perfect storm" of metabolic, mechanical, and inflammatory insults challenges vascular health, leading to cardiovascular mortality rates that approach 20% per annum (7). Perturbations in parathyroid hormone (PTH) production that compromise normal bone formation increase the risk for vascular calcium load (8,9). Indeed, in patients stage 5 chronic kidney disease, low-turnover osteoporosis with inappropriately normal PTH levels is a strong risk factor for vascular calcium accumulation (9). Vascular calcification contributes to vascular stiffening-abnormal aortofemoral Windkessel physiology that generates systolic hypertension, increases myocardial workload, and compromises distal tissue perfusion (10).In this issue of JASN, London et al. (11) again advance our understanding of human arterial physiology and calciotropic hormones, highlighting the importance of adequate vitamin D nutrition to maintenance of vascular structure and function in ESRD (8). As expected (10), age and hypertension strongly contribute to risk for reduced arterial compliance, evidenced by reduced brachial artery (BA) distensibility, increased aortic pulse wave velocity (PWV), and diminished flow-mediated dilation (FMD). As a sensitive index of perturbed intimal-medial signaling, reduced FMD identifies and confirms dysfunction in arterial physiology (10). The BA distensibility relationship also is important; this assessment of arterial compliance is not altered significantly by blood's rheologic properties and, like PWV, quantifies how vascular material and geometric properties integrate to determine arterial stiffnes...

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1α-Hydroxylase transactivation by γ-interferon in murine macrophages requires enhanced C/EBPβ expression and activation

Cited by 47 publications

References 24 publications

EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

Calciotropic Hormones and Arterial Physiology

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